Thrombosis and thromboembolism, in particular deep vein thrombosis (DVT) and pulmonary embolism (PE), are common clinical conditions that are associated with significant morbidity and mortality. It has been estimated that in the U.S. approximately 5 million patients experience one or more episodes of DVT per year and that over 500,000 cases of pulmonary embolism occur, resulting in 100,000 deaths. It has also been estimated that over 90% of all pulmonary emboli arise from DVT in the lower extremities. Anticoagulant therapy can effectively treat these conditions if applied early enough. However, such treatment is associated with risks (e.g. internal bleeding) that prevent unnecessary prophylactic application. More advanced techniques of thrombolytic intervention (such as the administration of recombinant tissue plasminogen activator or streptokinase) can be used in acute cases, but these techniques carry even greater risk. Moreover, effective clinical application of these techniques requires that the site of the offending thrombus be identified so as to monitor the effect of treatment.
For these reasons, a rapid means of localizing thrombi in vivo, most preferably using non-invasive methods, is highly desirable. In the past, contrast venography and compression B-mode ultrasound have been used to identify sites of deep-vein thrombosis; the choice of which technique was used depended on the expected location of the thrombus. However, the former technique is invasive, and both techniques are uncomfortable for the patient. In addition, these methods are in many cases either unsuitable or yield inaccurate results. Current methods used to diagnose PE include chest X-ray, electrocardiogram (EKG), arterial oxygen tension, perfusion and ventilation lung scans, and pulmonary angiography. Apart from the latter (invasive) procedure, none of these methods is capable of providing an unequivocal diagnosis.
Recently, a .sup.99m Tc-radiolabeled peptide, apcitide, which binds to the GPIIb/IIIa receptor on platelets, a component of thrombi, thereby providing an imaging agent specifically targeted to thrombi, completed clinical trials for scintigraphic imaging of acute DVT. A kit for making .sup.99m Tc-radiolabeled apcitide, ACUTECT.TM., is in the process of obtaining approval for sale as a radiopharmaceutical product. ACUTECT.TM. is formulated with bibapcitide, the chemical structure of which is set forth below. ##STR1## Bibapcitide and radiolabeling thereof are described in commonly assigned U.S. Pat. Nos. 5,508,020 and 5,645,815; in commonly assigned, copending U.S. Ser. No. 08/253,317, now U.S. Pat. No. 5,830,856; and in WO 93/23085; WO 93/25244; WO 94/23758 and WO 95/33496. Commonly assigned WO 94/07918 discloses that bibapcitide may also be used in unlabeled form as an antithrombotic agent.
Bibapcitide is a dimer of the monomer apcitide, which is also disclosed in the above-identified U.S. patents and application and international patent applications. The dimer bibapcitide is formed through a bismaleimide linkage of the carboxy-terminal cysteines of the two apcitide monomers. Monomeric apcitide has been complexed with .sup.99 TcO, and the apcitide/.sup.99 Tc complex has been characterized, in Zheng, et al., Abstract 336, 213th American Chemical Society Meeting, Apr. 13-17, 1997.